Dopamine (DA) is an important neurotransmitter in the central nervous system (CNS). Disturbances in dopaminergic signaling has been implicated in a number of neurobehavioral disorders such as schizophrenia, mania, depression, Parkinson's disease, movement and hyperactivity disorders and substance abuse. The actions of DA are mediated by five major subtypes of receptors, D1-D5. These receptors are seven transmembrane G-protein coupled receptors and have been broadly classified into D1-like receptors (D1 and D5) that couple positively to adenylyl cyclase and D2-like receptors (D2, D3 and D4) that couple negatively to adenylyl cyclase. Among the DA receptors, ligands that interact preferentially with the D3 subtype have attracted considerable attention as a drug development target in recent years (Hackling, A. E. et al. Chem Bio Chem. 2002, 3, 946-961; Joyce, J. N. et al. Drug Discov. Today 2005, 10, 917-925; Heidbreder, C. A. et al. Brain Res. Rev. 2005, 49, 77-105; Newman, A. H. et al. J. Med. Chem. 2005, 48, 3663-3679; Micheli, F. et al. Recent Patents CNS Drug Discov. 2006, 1, 271-288; Sokoloff, P. et al. CNS. Neurol. Disord. 2006, 5, 25-43; Boeckler, F. et al. Biochim. Biophys. Acta 2007, 1768, 871-887; Zhang, A. et al. Chem. Rev. 2007, 107, 274-302; Heidbreder, C. CNS Neurol. Disord. 2008, 7, 410-421; Heidbreder, C. A. and Newman, A. H. Ann. N.Y. Acad. Sci. 2010, 1187, 4-34; Löber, S. et al. Trends Pharmacol. Sci. 2011, 32, 148-157; Micheli, F. Chem Med Chem. 2011, 6, 1152-1162). In contrast to D2 receptors that are predominantly expressed in the basal ganglions, the D3 receptors are mainly found in mesolimbic system that control emotional and cognitive processes. D3 receptors are elevated in mesolimbic regions of schizophrenic patients. Therefore, inhibition of D3 binding sites is expected to attenuate positive symptoms associated with schizophrenia without causing extrapyramidal side effects associated with classical D2 antagonists. Moreover, D3 antagonists have been shown to enhance D3 receptor mediated release of acetylcholine in the frontal cortex and are therefore expected to have beneficial effect on attention and memory thus improving the negative symptoms of schizophrenia (Lacroix, L. P. et al. Neuropsychopharmacol. 2003, 28, 839-849). Recent preclinical studies with D3 selective or D3 preferring antagonists have confirmed the effectiveness of D3 ligands as active in models of antipsychotic properties (Millan, M. J. et al. J. Pharmacol. Exp. Ther. 2008, 324, 1212-1226; Millan, M. J. et al. Int. J. Neuropsychopharmacol. 2010, 13, 1035-1051; Agai-Csongor, E. et al. Bioorg. Med. Chem. Lett. 2007, 17, 5340-5344 and 2012, 22, 3437-3440).
Studies in animal models have demonstrated that D3 receptor activation is involved in the reinforcing effects and self-administration of cocaine. Long-term exposure to cocaine results in upregulation of D3 receptors as demonstrated in postmortem studies of cocaine-overdose fatalities, and PET studies have shown upregulation of D3R over D2R in methamphetamine polydrug abusers. These observations suggested that D3R antagonism may be an effective strategy in the pharmacotherapy of addiction. Indeed, growing preclinical evidence with a number of D3R selective antagonist or partial agonist ligands have confirmed that these D3R ligands can effectively suppress motivation to self-administer drugs and prevent drug-associated cue-induced craving and relapse to drug taking. Recently D3 selective antagonists such as GSK598809 and GSK618334 have been investigated in Phase 1 clinical trials for their development as drugs for the treatment of substance dependence and alcoholism (Löber, S. et al. Trends Pharmacol. Sci. 2011, 32, 148-157; Newman, A. H. et al. Biochem. Pharmacol. 2012, 84, 882-890).
The development of dopamine D3 receptor ligands with selectivity over D2 receptor has been a considerable challenge due to the high degree of structural homology between these two receptors. There is 90% sequence similarity between these two receptors in their predicted transmembrane regions (Sibley, D. R. et al. Trends Pharmacol. Sci. 1992, 13, 61-69). The orthosteric ligand binding site in these two receptors is highly similar to each other with only two amino acid differences in the 21 residues that form the binding site crevice. Recent studies with X-ray crystal structure of D3 receptor and with models of D3 and D2 receptor-ligand complexes indicate that the selectivity of some of the reported D3 ligands may be attributable to the differential interaction of aromatic end groups, tethered to the orthosteric binding moiety, at the accessory binding pocket located at the interface of TM1, 2, 3, 7 and extracellular loops (EL1 and EL2) of D3 and D2 receptors (Chien, E. Y. T. et al. Science 2010, 330, 1091-1095; Banala, A. K. et al. J. Med. Chem. 2011, 54, 3581-3594; Newman, A. H. et al. J. Med. Chem. 2012, 55, 6689-6699). Arylpiperazines or heteroarylpiperazines tethered to hteroaromatic end groups have previously been described as dopamine receptor ligands in publications and patents (Reviews: Hackling, A. E. et al. Chem Bio Chem. 2002, 3, 946-961; Newman, A. H. et al. J. Md. Chem. 2005, 48, 3663-3679; Micheli, F. et al. Recent Patents CNS Drug Discov. 2006, 1, 271-288; Boeckler, F. et al. Biochim. Biophys. Acta 2007, 1768, 871-887; Zhang, A. et al. Chem. Rev. 2007, 107, 274-302; Heidbreder, C. A. and Newman, A. H. Ann. N.Y. Acad. Sci. 2010, 1187, 4-34; Löber, S. et al. Trends Pharmacol. Sci. 2011, 32, 148-157; Micheli, F. Chem Med Chem. 2011, 6, 1152-1162. Geneste, H. et al. Bioorg. Med. Chem. Lett. 2006, 16, 490-494, 658-662 and 1934-1937. WO 2003028728, DE 10311065, DE 19735410, WO 2005056546, WO 2006015737, WO 2006015842, US 2008051409). Structure activity relationship (SAR) analysis on the binding selectivity and functional activity of such ligands indicate that these profiles are influenced both by the piperazine moiety that binds to the orthosteric binding site as well as by the aromatic end group that occupies the accessory binding pocket. Hence the prediction of affinity and selectivity profile of ligands possessing, for example, a piperazine head group tethered to an aromatic tail group remains difficult and not obvious.